Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “modulators”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 181 records · Page 10Linked to original sources
PubMed2004

The effect of endogenous modulator endobain E on NMDA receptor is interfered by Zn2+ but is independent of modulation by spermidine.

A brain endogenous factor, termed endobain E, allosterically decreases [3H]dizocilpine binding to NMDA receptor. Such effect depends on receptor activation by the coagonists glutamate and glycine and is interfered by channel blockers, suggesting its interaction with the inner surface of the associated channel. To further analyze endobain E effect on NMDA receptor, in the current study competitive [3H]dizocilpine binding assays to brain membranes were performed with Zn2+ to block the associated channel, as well as with spermidine (SPD), which exerts positive allosteric modulation of NMDA receptor. Partially or nonadditive effects on [3H]dizocilpine binding were recorded, respectively, in the presence of endobain E at a concentration that inhibits binding 25% plus IC25 Zn2+ or endobain E at a concentration that inhibits binding 50% plus IC50 Zn2+. With an endobain E concentration that decreases 25% ligand binding, SPD potentiated binding over a wide concentration range but failed to modify endobain E effect. Similarly, [3H]dizocilpine binding reduction over a wide endobain E concentration range remained unaltered by high SPD concentrations. Additive effects were observed with endobain E at a concentration that decreases binding 25% plus IC25 SPD site antagonists arcaine or ifenprodil. Zn2+ experiments indicated that endobain E effect is interfered by channel blockade produced by this ion. Although endobain E effect is dependent on NMDA receptor activation by glutamate and glycine, it proves independent of the positive modulation exerted by SPD. Thus the endogenous modulator seems not to interact at NMDA receptor polyamine site, favoring the hypothesis that endobain E binds inside the associated channel.

Animals↗
PubMed2003

Detection of amplitude modulation and frequency modulation in tactual gratings: a critical bandwidth for active touch.

Since most natural surfaces are complex and vary in amplitude and spatial frequency, it might be interesting to consider gratings not in the spatial domain, but in the spatial-frequency domain. Detection thresholds for amplitude modulation (AM) and frequency modulation (FM) in sinusoidal gratings were measured for seven participants. Participants moved their fingers actively across the gratings. Although the two types of modulation are quite different in the spatial domain, they have many features in common in the frequency domain. In previous research (Nefs et al 2001 Perception 30 1263-1274) we measured the discrimination thresholds for amplitude and frequency for sinusoidal gratings. We hypothesised then that these thresholds could be used to predict the discriminability of other types of gratings. In the present study, we did indeed find that the FM and AM detection thresholds can be understood quite well by these discrimination thresholds. The results indicate that the tactual system contains parallel psychophysical channels that filter and integrate the power of stimuli within critical bands. With these results, we are also able to calculate the critical bandwidth for active dynamic touch. We estimated the critical bandwidth surrounding the spatial frequency of 2 cycles cm(-1) to be about 125% of that spatial frequency. This value for the critical band for spatial frequency is incompatible with previous findings for temporal frequencies in vibrotactile research. This indicates that dynamic spatial-frequency discrimination is not likely to be done by temporal frequency.

Adult↗
PubMed2006

Identification of putative androgen receptor interaction protein modules: cytoskeleton and endosomes modulate androgen receptor signaling in prostate cancer cells.

We have developed a novel androgen receptor (AR) expression system in the 293 human embryonic kidney cell line that recapitulates AR biochemical activity as a steroid hormone receptor in prostate cancer cells. We used this system to identify putative AR-binding proteins in the cytosolic and nuclear compartments of mammalian cells using a large scale co-immunoprecipitation strategy coupled to quantitative mass spectrometry. For example, the heat shock 70 and 90 chaperones, which are known regulators of steroid hormone receptor, were identified as AR-binding proteins. AR purification enriched for proteins involved in RNA processing, protein transport, and cytoskeletal organization, suggesting a functional link between AR and these protein modules in mammalian cells. For example, AR purification in the nuclear compartment led to the specific enrichment of alpha-actinin-4, clathrin heavy chain, and serine-threonine protein kinase C delta. Short interfering RNA knockdown studies and co-transcriptional reporter assays revealed that clathrin heavy chain possessed co-activator activity during AR-mediated transcription, whereas alpha-actinin-4 and protein kinase C delta displayed both co-activator and co-repressor activity during AR-mediated transcription that was dependent upon their relative expression levels. Lastly immunohistochemical staining of prostate tissue showed that alpha-actinin-4 levels decreased in the nucleus of high grade cancerous prostate samples, suggesting its possible deregulation in advanced prostate cancers as previously observed in late stage metastatic breast cancers. Taken together, these findings suggest AR binds to specific protein modules in mammalian cells and that these protein modules may provide a molecular framework for interrogating AR function in normal and cancerous prostate epithelial cells.

Androgen-Binding Protein↗
PubMed2004

Intensity-modulated radiation therapy: overlapping co-axial modulated fields.

The Varian multi-leaf collimator has a 14.5 cm leaf extension limit from each carriage. This means the target volumes in the head and neck region are sometimes too wide for standard width-modulated fields to provide adequate dose coverage. A solution is to set up asymmetric co-axial overlapping fields. This protects the MLC carriage while in return the MLC provides modulated dose blending in the field overlap region. Planar dose maps for coincident fields from the Pinnacle radiotherapy treatment planning system are compared with planar dose maps reconstructed from radiographic film and electronic portal images. The film and portal images show small leaf-jaw matchlines at each field overlap border. Linear profiles taken across each image show that the observed leaf-jaw matchlines from the accelerator images are not accounted for by the treatment planning system. Dose difference between film reconstructed electronic portal images and planning system are about 2.5 cGy in a modulated field at d(max). While the magnitude of the dose differences are small improved round end leaf modelling combined with a finer dose calculation grid may minimize the discrepancy between calculated and delivered dose.

Film Dosimetry↗
PubMed1988

Norepinephrine and calcium responses to altered sodium intake in modulating and non-modulating high-renin hypertension.

Sodium sensitivity in subjects with high-renin hypertension has been associated with non-modulation of cardiovascular and biochemical responses to alteration in sodium intake. Using the percentage suppression of plasma renin activity in response to an increase in dietary sodium intake, high-renin hypertensive subjects were categorized in two groups. In association with the increase in sodium intake, modulators showed greater than 58% suppression of plasma renin activity, and significant reductions in mean arterial pressure, plasma aldosterone, norepinephrine and serum calcium concentration. Non-modulators had no significant change in plasma renin activity, mean arterial blood pressure, plasma aldosterone, norepinephrine or serum calcium concentration. The blood pressure response to an increase in dietary sodium intake may be a composite of responses of the renin-angiotensin-aldosterone axis, the adrenergic nervous system and calcium regulatory system.

Aldosterone↗
PubMed2005

Noise-induced escape of periodically modulated systems: from weak to strong modulation.

Noise-induced escape from a metastable state is studied for an overdamped periodically modulated system. We develop an asymptotic technique that gives both the instantaneous and period-average escape rates, including the prefactor, for an arbitrary modulation amplitude A . We find the parameter range where escape is strongly synchronized and the instantaneous escape rate displays sharp peaks. The peaks vary with increasing modulation frequency or amplitude from Gaussian to strongly asymmetric. The prefactor nu in the period-average escape rate depends on A nonmonotonically. Near the bifurcation amplitude A(c) it scales as nu approximately (A(c) - A)(zeta). We identify three scaling regimes, with zeta = 1/4, -1, and 1/2.

Journal Article↗
PubMed2005

Modulated optical structures over a modulationally stable medium.

Evidence of modulated dissipative structures with an intrinsic wavelength in a nonlinear optical system devoid of Turing instability is given. They are found in the transverse field distribution of an optical cavity containing a liquid crystal light valve. Their existence is related to a transition from flat to modulated fronts connecting the unstable middle branch of a bistability cycle and either of the two stable uniform states. We first analyze the cavity in the limit of nascent bistability, where a modified Swift-Hohenberg equation is derived. This allows for a simple analytical expression of the threshold associated with the transition as well as the wavelength of the emerging structure. Numerical simulations show development of ring-shaped modulated fronts and confirm analytical predictions. We then turn to the full model and find the same transition, both analytically and numerically, proving that this transition in not limited to nascent bistability regimes.

Journal Article↗
PubMed2006

Description of Ba(1 + x)Ni(x)Rh(1 - x)O3 with x = 0.1170 (5) in superspace: modulated composite versus modulated-layer structure.

The structure of the compound Ba(1 + x)Ni(x)Rh(1 - x)O3 [x = 0.1170 (5)] has been analyzed at room temperature within the (3 + 1)-dimensional superspace approach using single-crystal X-ray diffraction data. Two different models are presented, the compound is refined as modulated composite as well as modulated-layer structure. In both models discontinuous atomic domains are applied to describe the structural modulations. While the first approach stresses the pseudo-one-dimensional constitution, the latter highlights the layered character of these structures.

Journal Article↗
PubMed1984

Modulation of phosphorylation of a 30-kD polyribosomal protein (pp30) by ACTH and spermine: comparison with modulation of brain protein synthesis.

Gel electrophoretic separation of proteins phosphorylated in a postmitochondrial supernatant fraction of brain in the presence of spermine or adrenocorticotropin (ACTH) indicated modulation in only one region (30 kD) of the gel. The 30-kD (pp30) protein together with enzyme activity catalyzing its phosphorylation and sensitivity of the phosphorylation to spermine and ACTH were retained in a free polyribosomal fraction of this extract. ACTH(11-24) inhibited phosphorylation at all the spermine or Mg2+ concentrations tested. Structure-activity studies revealed that the inhibitory activity within ACTH(1-24) resides in the sequences ACTH(11-24), (5-18, 17Lys, 18Lys)-NH2, (15-24), (7-16)-NH2, and (1-16)-NH2 and can also be found in certain polylysine fragments. Phosphorylation under conditions suitable for measuring protein synthesis revealed only one phosphoprotein (pp30), sensitive to both ACTH(15-24) and spermine. The possibility of a relationship between modulation of pp30 phosphorylation and modulation of brain cell-free protein synthesis is discussed in relation to the effects of ACTH, spermine, and Mg2+.

Adrenocorticotropic Hormone↗
PubMed2005

Modulation of the homophilic interaction between the first and second Ig modules of neural cell adhesion molecule by heparin.

The second Ig module (IgII) of the neural cell adhesion molecule (NCAM) is known to bind to the first Ig module (IgI) of NCAM (so-called homophilic binding) and to interact with heparan sulfate and chondroitin sulfate glycoconjugates. We here show by NMR that the heparin and chondroitin sulfate-binding sites (HBS and CBS, respectively) in IgII coincide, and that this site overlaps with the homophilic binding site. Using NMR and surface plasmon resonance (SPR) analyses we demonstrate that interaction between IgII and heparin indeed interferes with the homophilic interaction between IgI and IgII. Accordingly, we show that treatment of cerebellar granule neurons (CGNs) with heparin inhibits NCAM-mediated outgrowth. In contrast, treatment with heparinase III or chondroitinase ABC abrogates NCAM-mediated neurite outgrowth in CGNs emphasizing the importance of the presence of heparan/chondroitin sulfates for proper NCAM function. Finally, a peptide encompassing HBS in IgII, termed the heparin-binding peptide (HBP), is shown to promote neurite outgrowth in CGNs. These observations indicate that neuronal differentiation induced by homophilic NCAM interaction is modulated by interactions with heparan/chondroitin sulfates.

Animals↗
PubMed2005

Atypical muscarinic allosteric modulation: cooperativity between modulators and their atypical binding topology in muscarinic M2 and M2/M5 chimeric receptors.

The binding and function of muscarinic acetylcholine receptors can be modulated allosterically. Some allosteric muscarinic ligands are "atypical", having steep concentration-effect curves and not interacting competitively with "typical" allosteric modulators. For atypical agents, a second allosteric site has been proposed. Different approaches have been used to gain further insight into the interaction with M2 receptors of two atypical agents, tacrine and the bispyridinium compound 4,4'-bis-[(2,6-dichloro-benzyloxy-imino)-methyl]-1,1'-propane-1,3-diyl-bispyridinium dibromide (Duo3). Interaction studies, using radioligand binding assays and the allosteric ligands obidoxime, Mg2+, and the new tool hexamethonium to antagonize the allosteric actions of the atypical ligands, showed different modes of interaction for tacrine and Duo3 at M2 receptors. A negatively cooperative interaction was observed between hexamethonium and tacrine (but not Duo3). A tacrine dimer that exhibited increased allosteric potency relative to tacrine but behaved like a typical allosteric modulator was competitively inhibited by hexamethonium. M2/M5-receptor mutants revealed a dependence of tacrine and Duo3 affinity on different receptor epitopes. This was confirmed by docking simulations using a three-dimensional model of the M2 receptor. These showed that the allosteric site could accommodate two molecules of tacrine simultaneously but only one molecule of Duo3, which binds in different mode from typical allosteric agents. Therefore, the atypical actions of tacrine and Duo3 involve different modes of receptor interaction, but their sites of attachment seem to be the "common" allosteric binding domain at the entrance to the orthosteric ligand binding pocket of the M2-receptor. Additional complex behavior may be rationalized by allosteric interactions transmitted within a receptor dimer.

Allosteric Regulation↗
PubMed2006

A novel class of positive allosteric modulators of metabotropic glutamate receptor subtype 1 interact with a site distinct from that of negative allosteric modulators.

We recently reported a novel class of compounds, represented by 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CD-PPB), that act as positive allosteric modulators (potentiators) of metabotropic glutamate receptor (mGluR) subtype 5. Studies of CDPPB analogs revealed that some compounds in this series serve also as positive allosteric modulators of mGluR1. Although CDPPB is selective for mGluR5 relative to other mGluR subtypes, several CDPPB analogs also showed 2.5-fold potentiation of glutamate-induced calcium transients in cells expressing mGluR1 at 10 muM, with 4-nitro-N-(1,4-diphenyl-1H-pyrazol-5-yl)benzamide (VU-71) being selective for mGluR1. In previous studies, we found that two structural classes of mGluR5-selective allosteric potentiators, including CDPPB, share a common binding site with the allosteric mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine. Negative allosteric modulators of mGluR1, regardless of structural class, have been reported to bind to a common allosteric antagonist site on this receptor. However, neither the novel CDPPB analogs nor previously identified allosteric mGluR1 potentiators [e.g., (S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine (Ro 67-7476), ethyl diphenylacetylcarbamate (Ro 01-6128), and butyl (9H-xanthene-9-carbonyl)carbamate (Ro 67-4853)] displaced the binding of [(3)H]1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone (R214127), a high-affinity radioligand for the allosteric antagonist site on mGluR1 at concentrations several orders of magnitude higher than those required to induce allosteric potentiation of mGluR1 responses. These data suggest that allosteric potentiators of mGluR1 act at a site that is distinct from that of allosteric antagonists of mGluR1. Site-directed mutagenesis revealed that valine at position 757 in transmembrane V of mGluR1a is crucial for the activity of multiple classes of allosteric mGluR1 potentiators.

Allosteric Regulation↗
PubMed2002

Second-line chemotherapy with a hybrid-alternating regimen of bolus 5FU modulated by methotrexate and infusional 5FU modulated by folinic acid in patients with metastatic colorectal cancer pretreated with 5FU. A phase 2 study.

BACKGROUND AND AIM: In vitro, methotrexate (MTX) is the best modulator for bolus 5-fluorouracil (5FU), whereas folinic acid (FA) is the best for continuous infusion. We evaluated the effect of 5FU modulated by both MTX (bolus administration) and FA (continuous infusion) as second-line treatment of patients with metastatic colorectal cancer. PATIENTS AND METHODS: Entry criteria were: at least one 5FU-based chemotherapy regimen as first-line treatment for metastatic disease, or progression within twelve months after 5FU-containing adjuvant therapy. Treatment schedule: MTX 200 mg/m2 i.v. days 1 and 15; 5FU 600 mg/m2 i.v. bolus, days 2 and 16; 5FU 200 mg/m2 i.v. continuous infusion for 21 days, starting on day 29; FA 20 mg/m2 i.v. bolus weekly during the three weeks of 5FU infusion. Cycles were repeated every 56 days. The primary end-point was tumour control rate, including partial responses and stabilizations. RESULTS: 34/35 patients enrolled were evaluable for response. Five (14.7%) had a partial response, 13 (38.2%) disease stabilization, and 16 (47.1%) progressed; tumour control rate was 52.9%. Median TTP was 5.8 months (95% CI 4.03-7.83); 29 patients had died. Median OAS was 15.9 months (95% CI 8.8-21.9). Toxicity was mild. CONCLUSIONS: The regimen constituted by 5FU modulated by MTX (bolus administration) and FA (continuous infusion) is active as second-line treatment of metastatic colorectal cancer.

Adenocarcinoma↗
PubMed2004

Hormonal modulation of singing: hormonal modulation of the songbird brain and singing behavior.

During the past three decades research on the hormonal control of singing has fundamentally altered our basic concepts about how hormones modulate brain function and activate behavior. Exciting discoveries first documented in songbird brains have since been documented in a wide variety of vertebrate species, including humans. Circulating hormones organize sexual dimorphisms in brain structure during development, activate changes in brain structure during adulthood, and modulate the addition of new neurons in the adult brain. The brain has proved to be the primary source of estrogens in general circulation in adult male finches. Studies of the hormonal modulation of singing are complicated by multiple sites of hormone production, multiple sites of hormone action, hormone metabolism by different tissues, the involvement of a variety of hormones, and the effects of social context. This chapter provides a brief review of these topics, as well as a brief overview of techniques used to study endocrine mechanisms controlling behavior.

Animals↗
PubMed2005

Generation of flat power-envelope terahertz-wide modulation sidebands from a continuous-wave laser based on an external electro-optic phase modulator.

Flat power-envelope terahertz-wide modulation sidebands are generated by only electro-optic phase modulation of continuous-wave laser light. Generation and power equalization of widespread sidebands are realized simultaneously by spatial distribution of the modulation index within a laser beam cross section by use of simple domain-engineering processes in LiTaO3 electro-optic crystal. Generation of 46 sidebands spaced by 16.25 GHz within a -3-dB bandwidth (over a 1-THz span for a +/- 3-dB bandwidth) is demonstrated.

Journal Article↗
PubMed2002

The col-1 module of human matrix metalloproteinase-2 (MMP-2): structural/functional relatedness between gelatin-binding fibronectin type II modules and lysine-binding kringle domains.

Human matrix metalloproteinase-2 (MMP-2) contains three in-tandem fibronectin type II (FII) repeats that bind gelatin. Here, we report the NMR solution structure of the first FII module of MMP-2 (col-1). The latter is described as a characteristic, globular FII fold containing two beta-sheets, a stretch of 3(1)-helix, a turn of alpha-helix, and an exposed hydrophobic surface lined with aromatic residues. We show that col-1 binds (Pro-Pro-Gly)6, a mimic of gelatin, with a Ka of approx. 0.42 mm(-1), and that its binding site involves a number of aromatic residues as well as Arg34, as previously found for the second and third homologous repeats. Moreover, the affinity of the in-tandem col-1+2 construct (col-12) toward the longer ligand (Pro-Pro-Gly)12 is twice that for (Pro-Pro-Gly)6, as expected from mass action. A detailed structural comparison between FII and kringle domains indicates that four main conformational features are shared: two antiparallel beta-sheets, a central 3(1)-helix, and the quasiperpendicular orientation of the two proximal Cys-Cys bonds. Structure superposition by optimizing overlap of cystine bridge areas results in close juxtaposition of their main beta-sheets and 31-helices, and reveals that the gelatin binding site of FII modules falls at similar locations and exhibits almost identical topological features to those of the lysine binding site of kringle domains. Thus, despite the minor (<15%) consensus sequence relating FII modules to kringles, there is a strong folding and binding site structural homology between the two domains, enforced by key common conformational determinants.

Amino Acid Sequence↗
PubMed2003

[Objective audiometry using amplitude-modulation following responses elicited by compound sinusoidal amplitude-modulated tones].

The amplitude-modulation following response (AMFR) test is an ideal tool for objective audiometry because of its high frequency specificity. However, this examination is time-consuming when hearing thresholds at several frequencies must be tested, even if the thresholds are automatically detected using computer techniques like phase spectral analysis. To solve this problem, a multiple stimulation technique using a compound sinusoidal amplitude-modulated tone (compound SAM tone) was used to detect 40 Hz AMFR thresholds at several frequencies. A technique for analyzing the thresholds determined by the AMFR elicited by compound SAM tones was established using the component synchrony measure method, a type of phase spectral analysis. The usefulness of this technique was then evaluated. The difference between the thresholds for the AMFR to compound SAM tones and the AMFR to simple SAM tones was clinically negligible. No difference in the threshold of the AMFR was observed when the carrier frequency and modulation frequency combinations of the 4 SAM tones, components of the compound SAM tone, were altered. The threshold pattern of the 40 Hz AMFR detected using the multiple stimulation technique closely resembled the corresponding audiogram patterns for all types of adult hearing impairments. These findings suggest that AMFR using the multiple stimulation technique has almost the same level of frequency specificity as the AMFR elicited by simple SAM tones. The time required to test the AMFR thresholds for four frequencies was, on average, about 24 minutes per ear, which was markedly shorter than the time required using simple SAM tones. AMFR detected using the multiple stimulation technique thus appears to have a high frequency specificity and to be potentially useful for objective audiometry.

Adult↗
PubMed1986

Amplitude modulation of EPSPs in motoneurons in response to a frequency-modulated train in single la afferent fibers.

In anesthetized cats, single group Ia fibers were activated with a train of 52 stimuli whose interspike intervals were obtained from the discharge of a group Ia fiber in a walking cat (courtesy of Dr. G. E. Loeb, NIH). The EPSPs recorded in motoneurons to which the afferents projected were averaged in register (EPSP1, EPSP2, ..., EPSP52) in response to multiple presentations of the train at a rate (0.77 Hz) similar to the stepping rate of the cat. Amplitudes of these averaged EPSPs were found to be highly variable, depending both on afferent discharge rate and history of activation. The initial EPSP was generally potentiated, and EPSPs in the high-frequency (greater than 200 Hz) middle portion of the train were generally reduced in amplitude. Connections at which the first EPSP was most potentiated tended to be those which showed the most depression of EPSP amplitude during the high-frequency portion of the train. Thus, at some connections, modulation of EPSP amplitude during the frequency-modulated train was much greater than at other connections. In general, the extent of modulation was greater on low-rheobase motoneurons than on high-rheobase motoneurons. We suggest that these differences in transmission permit type S (i.e., low-rheobase) motoneurons, which on average generate the largest EPSPs, to reach threshold at low levels of input (size principle) but prevent excessive depolarization due to temporal summation during high-frequency stimulation.

Afferent Pathways↗